Transforming growth factor fi receptor type II (TGFBR2) is a tumor suppressor gene that is commonly mutated in colon cancer, and its inactivation plays an important and potentially paradoxical role in colon carcinogenesis. TGFBR2 is an essential component of the TGF-fi receptor complex, which mediates the effects of the multi-functional cytokine, TGF-fi. TGF-fi and TGFBR2 regulate a variety of cell functions including cell growth, senescence, differentiation; extracellular matrix remodeling, and genomic stability. Thus, TGFBR2 inactivation likely affects tumor formation through a variety of mechanisms, including excess cell proliferation, increased cell invasiveness, regulation of genomic stability, etc.. Interestingly, unlike classical hormones whose actions are few and specific, TGF-IJ can cause these myriad effects on a cell because TGF-fi's effects depend on the type and state of the cell, termed the 'cellular context'. Our preliminary data demonstrates that the cellular context dependence of TGF-fi's effects dictates the consequences of the loss of TGF-fi signaling in colon cancer and that those consequences are a result of cooperation of TGFBR2 inactivation with other genes commonly mutated in colon cancer. We now propose to study the effects of TGFBR2 inactivation in the context of known genetic events that occur in colon cancer (e.g. ARC, KRAS2, and TRP53 mutations). We will employ novel model systems to determine how TGFBR2 inactivation affects tumor cell behavior, especially in the context of mutant APC, KRAS2, and TP53 . Of note, these studies have yielded novel genetic models for the classic adenoma-cancer pathway and an unprecedented model for the hyperplastic polyp-cancer path. The Specific Aims are as follows: Aim 1) To determine the effect of TGF-fi signaling pathway inactivation in the setting of Ape mutation and Wnt signaling activation on intestinal cancer formation. Aim 2) To determine if TGF-fi signaling pathway inactivation cooperates with Kras2 mutation and Ras-Raf pathway activation in intestinal cancer formation. Aim 3) To determine the in vivo consequences of TGFBR2 inactivation on colon cancer initiation and progression using novel mouse models of intestinal cancer that genetically recapitulate human colon cancer, Apc1638N;LSL-Kras2G12D ;Tgfbr2IEKO, and Apc1638N;LSL-Trp53R172H;Tgfbr2IEKO mice